Lupus is an autoimmune disease that affects over a million people in the United States, disproportionately affecting women of childbearing age. It is difficult to treat and the few effective therapies have significant toxicities and side effects. The abnormal activation of two types of immune system cells, B lymphocytes and plasmacytoid dendritic cells are important in the pathogenesis of the disease. The chronic activation of both cell types appears due to stimulation by DNA and RNA acting through the innate immune receptors, TLR7 and TLR9. We have developed a series of synthetic oligonucleotides (termed IRS) with sequence motifs strongly inhibitory for both TLR7 and TLR9 signaling. The lead IRS molecule, DV056, has been proven active in mouse models of systemic lupus erythematosus and IND-enabling studies are underway to support an indication in systemic lupus. Recent evidence now points to a role for plasmacytoid dendritic cells in cutaneous lupus and in a series of related cutaneous autoimmune diseases, including lichen planus dermatomyositis, lichen sclerosus and cutaneous GVHD. Our preliminary evidence suggests that this pathway of inflammation triggered by self DNA and RNA can be activated by repeated tape stripping of skin in normal mice. This proposal comprises several related activities to develop a preclinical model of cutaneous autoimmunity mediated by plasmacytoid dendritic cell activation and IFN-1 production. These studies include: " Definition of the role of key cell types and signaling pathways in inflammation caused by tape stripping in mice " Development of a chronic inflammation model using mice predisposed to autoimmune disease " Initial preclinical evaluation of IRS as an inhibitor of autoimmune inflammation induced by tape-stripping. The ultimate goal is to use the results of this work to support the development of IRS for autoimmune diseases with primary involvement in the skin. Because of the ease in evaluating symptoms, diseases such as cutaneous lupus may prove to be particularly useful for in the early clinical development of IRS. PUBLIC HEALTH RELEVANCE: Lupus is a serious autoimmune disease affecting over 1 million people in the U.S., primarily women. Current treatments for this disease have serious side effects;however recent discoveries suggest new methods of treatment that may be safer and more effective. We propose to develop a novel drug that inhibits Interferon-alpha, a key factor in the disease as a therapy for cutaneous lupus and related autoimmune diseases in the skin.